Magnetic resonance imaging assisted cryosurgery

ABSTRACT

Methods and apparatus for magnetic resonance imaging (MRI) assisted cryosurgery. Optimal probe placements and cooling parameters are calculated prior to cryosurgery using MRI data. A MRI compatible cryoprobe and a stereotactic probe positioning device are provided. The resolution of MR images is enhanced by mounting a radio frequency MR coil on the intracorporeal end of a cryoprobe. During cryosurgery the temperature distribution in the frozen region is solved by determining the boundary of the frozen region and solving the heat equation for the known boundary conditions. During cryosurgery the temperature distribution in the unfrozen region is determined by T1 measurements. The process of freezing is controled using information from the solution of the energy equation in the frozen region and temperature measurements in the unfrozen region. After cryosurgery the extent of the tissue damage may be ascertained using phosphorus-31 and/or sodium-23 spectroscopy with a special coil set on the cryosurgical probe.

BACKGROUND OF THE INVENTION

Cryosurgery is a common and effective surgical procedure in whichfreezing is used to destroy undesirable tissue. The procedure is used inmany areas of medicine such as dermatology, gynecology, otolaryngology,proctology, veterinary medicine. In cryosurgery, freezing is usuallyaccomplished by placing a metallic cryosurgical probe, insulated exceptat its tip, in contact with the subject tissue to be frozen. As theprobe is cooled internally (by either circulating a refrigerant(cryogen), Joule Thompson effects, Peltier effects, or by means of heatpipes) heat is removed from the tissue by conduction and a region offrozen tissue grows outward from the probe. When an adequate amount oftissue has been frozen, the flow of cryogen is stopped and the tissue isallowed to thaw.

One of the advantages of cryosurgery is that it can treat tumorsfocally. Small volumes can be destroyed using a thin needle-likecryosurgical probe, while larger volumes can be destroyed with largerprobes or multiple probes. Multiple sites may be treated in this mannerand irregularly-shaped volumes can be treated using multiple probes.Retreatment is possible if the disease recurs.

Because tissues can be treated focally, cryosurgery has the potential tospare more adjacent healthy tissue than resection, radiotherapy, orhyperthermia. Another advantage of cryosurgery is that it is easy tocontrol because the freezing process is relatively slow, usually on theorder of 1 mm/min. If the therapy is adequately monitored, freezing canbe halted before the freezing interface reaches sensitive tissues. Anadditional advantage of the slow freezing rate of cryosurgery is thatcapillaries freeze while larger vessels, which act as local heatsources, remain undamaged. Cryosurgery is therefore effective intreating otherwise unresectable solid tumors abutting large bloodvessels.

Cryosurgery has also been successfully used in the treatment of manybenign and malignant skin cancers. [Torre, D., "Cryosurgery of BasalCell Carcinoma," Journal of the American Academy of Dermatology, 1986;15(5):917-29.][Breitbart][Kuflik, A., et al., "Lymphocytoma Cutis: ASeries of Five Patients Successfully Treated with Cryosurgery," Journalof the American Academy of Dermatology, 1992; 26:449-52][Tappero, J.W.,et al., "Cryotherapy for Cutaneous Kaposi's Sarcoma (KS) Associated withAcquired Immune Deficiency Syndrome (AIDS); A Phase II Trial," Journalof Acquired Immune Deficiency Syndromes, 1991;4(9):83946][Dachow-Siwie'c, Elzbieta, "Treatment of Cryosurgery in thePremalignant and Benign Lesions of the Skin," Clinics in Dermatology1990; 8(1):69-79]. For lesions which are less than 3 mm in depth andbenign, the recommended treatment is a liquid nitrogen spray, open orconstrained by a neopreme cone barrier or otoscope cone [Torre, D.,"Cryosurgery of Basal Cell Carcinoma," Journal of the American Academyof Dermatology, 1986; 15(5):917-29.]]. The depth and lateral extent ofthe cryolesion is estimated by the surgeon to be some percentage of thelateral spread of the frozen region at the surface [Torre, D.,"Cryosurgery of Basal Cell Carcinoma," Journal of the American Academyof Dermatology, 1986; 15(5):917-29]. However, for tumors which aredeeper than 3 mm, or for malignant tumors, some surgeons prefer a closedprobe. It is recommended that some type of instrumentation be usedduring surgery in order to monitor the depth dose. Thermocouple tippedhypodermic needles are the most common method of instrumentation, butultrasound and electrical resistance/impedance measurements have alsobeen used. Though thermocouple measurements are the most common, theygive the surgeon only a rough idea of the zone of cold injury based onone or more discrete measurements. Single point measurements may be anineffective measure of the depth of the dose due to variations in fatcontent and thus the local tissue thermal conductivity, increased bloodflow in the region near the cryolesion [Bircher, A.J., Buchner, S.A.,"Blood Flow Response to Cryosurgery on Basal Cell Carcinomas," Acta DermVenereol (Stockholm) 1991; 71:531-3] or heat sources presented by mediumsized blood vessels.

MRI has been shown to be useful in determining skin lesion depths, andis recommended by Zemtsov et. al. for preoperative evaluation of lesions[Zemtsov, A., et al., "Magnetic Resonance Imaging of CutaneousNeoplasms: Clinicopathologic Correlation," Journal of DermatologicalSurgery and Oncology, 1991;17:416-22; Zemtsov, A., et al., "MagneticResonance Imaging of Cutaneous Melanocytic Lesions," Journal ofDermatological Surgery and Oncology, 1989; 15:854-58]. Zemtsov andcolleagues have demonstrated that several types of lesions can besuccessfully imaged using a commercially available General Electricbrand 1.5 Tesla NMR spectrometer, and have shown that NMR calculatedtumor depths correlate well with Breslow's measured depths.

The idea of using cold in medical therapeutics has been documented asearly as the third century BC but its use in treating tumors was firstattempted successfully during the last century by James Arnott.Contemporary cryosurgery can be traced to the early 1960's when Cooperand Lee developed a cryosurgical apparatus consisting of a hollow metaltube, vacuum insulated except at its tip, through which liquid nitrogenflowed [Ablin, R.J., Handbook of Cryosurgery, Marcel Dekker Inc., NewYork, 1980]. They treated Parkinsonism by freezing the basal gangliauntil the patient's tremor subsided. Although the treatment waseffective in providing palliation, it was replaced by drug therapy whenL-Dopa became clinically available. During the sixties and earlyseventies the cryosurgical treatment of skin lesions and lesions ofother tissues outside the body provided satisfactory results [Gage, A.,"Current Progress in Cryosurgery," Cryobiology 25:483-486, 1988.Rubinsky, B., Onik, G., "Cryosurgery: Advances in the Application of LowTemperature to Medicine," International Journal of Refrigeration, 14:1-10, 1991. However, enthusiasm waned for the technique after initialattempts to treat tumors deep in the body. The reasons for the reductionin interest in cryosurgery are due to two problems faced by surgeons:

1) Since the frozen region propagates from the probe into opaque tissueit is impossible to visually monitor the extent of the frozen region.This can result in either insufficient freezing, leaving undesirabletissues unfrozen, or too much freezing which can damage essentialtissues.

2) Since freezing itself does not always result in tissue damage, it isdifficult to estimate how much of the frozen tissue is actuallydestroyed.

Understandably, surgeons have been reluctant to use a technique in whichthey are unable to observe and control the immediate consequences oftheir actions. However, the latest advances in imaging technology havethe potential for overcoming the two problems noted above. In fact,intraoperative ultrasound technology has already facilitated cryosurgeryin the liver and prostate with good results [Onik, G., Ruinsky, B.,Zemel, R., Weaver, L., Diamond, D., Cobb, C., Porterfield, B.,"Ultrasound Guided Hepatic Cryosurgery in the Treatment of MetastaticColon Carcinoma; Preliminary Results," Cancer 67:901-907, 1991. Onik,G., Porterfield, B., Rubinsky, B., Cohen, J., "PercutaneousTransperineal Prostate Cryosurgery Using Transrectal UltrasoundGuidance: Animal Model," Urology 37:277-281; 1991.] However, ultrasonicmonitoring of cryosurgery which utilized the reflected pressure wavesfrom the freezing interface has drawbacks. First, ultrasound onlyprovides a planar section of the three-dimensional ice front. Second,the region behind the freezing interface (which reflects the pressurewaves) is in shadow and cannot be observed. In the liver, this problemcan be overcome by moving the ultrasound transducer to a differentlocation to obtain a different point of view. However, imaging of theprostate is only possible from a limited number of sites. Irregular icestructure in the prostate hidden from the ultrasonic monitoring canresult in complications such as urethrorectal or urethrocutaneousfistulas. Third, many organs such as the brain are not easily accessibleto ultrasound. Fourth, ultrasound shows only the position of thefreezing interface, but does not provide information concerning theextent of tissue damage.

Nuclear Magnetic Resonance (NMR) monitoring of cryosurgery cancircumvent many of the above-mentioned problems. NMR works by puttingthe sample in a strong static magnetic field, applying a transientmagnetic field to the nucleus of atoms in a target region and recordingthe radio frequency signals emitted as they revert to their unexcitedstate. The frequency is a function of the atom excited, the positionaland orientational relation between the atom and its neighbors in aparticular molecule and the local applied field. Therefore the emittedsignal can be used to determine the presence of certain atoms and theirchemical environment. The intensity of the signal can be correlated tothe amount of the investigated species present. Other factors alsoaffect the signal emitted, such as temperature or thermodynamic state.Some of the most important species studied in biological NMR areprotons, phosphorous, sodium, and carbon. NMR imaging can be used tomonitor freezing during cryosurgery and to optimize the cryosurgicalprocedure. NMR spectroscopy and spectroscopic imaging can also provideinformation concerning the relation between tissue that was frozen andtissue that is damaged.

MR imaging (MRI) is a promising tool for assisting cryosurgery forseveral reasons:

1. Prior to surgery, anatomical information of the region to be frozencan be obtained from MRI and used in cryosurgical treatment planning.The information can be used to model the freezing process and calculatethe optimal number of cryoprobes to use, the locations they should beplaced at, and the optimal freezing protocol. These procedures can beperformed not only with images from MRI but also with images fromultrasound CT, PET and other imaging techniques.

2. Fast, multiple-slice MRI can provide three or more planes acquired inless than 60 seconds, and can provide three-dimensional images of thefrozen region during cryosurgery. This provides adequate time resolutionto follow the freezing process and to make treatment protocol decisions.MRI imaging can be used to monitor the extent of freezing since ice isinvisible under proton NMR while unfrozen tissue is not. The transitionof water from liquid to solid is accompanied by large decreases in theproton NMR signal from the water since interactions that are averaged tonear zero by molecular tumbling in the liquid (motional narrowing)become significant in the solid thereby increasing relaxation rates byorders of magnitude. This makes water protons in ice invisible tostandard NMR imaging techniques and frozen regions appear black [Isoda,H., "Sequential MRI and CT Monitoring in cryosurgery--an experimentalstudy in polyvinyl alcohol gel," Panthom Nippon Igeku Hoshagen GakkaiZasshi, Nippon Acta Radiologica, 49:1096-1001, 1589 (in Japanese).Isoda, H., "Sequential MRI and CT monitoring in cryosurgery--anexperimental study in rats," Nippon Acta Radiologgia, 49:1499-1508,1989].

The minimum requirement for monitoring cryosurgery is that the positionof the freezing interface be ascertainable. Thus almost any NMR imagingmethod may be employed, including fast and ultra-fast methods such asFast Low-Flip Angle NMR (FLASH), echo-planar NMR, and radio frequencyspoiled gradient echo, i.e. a FLASH sequence with the transversecoherence spoiled by randomizing phase radio frequency pulses. [Cohen,M.S., and Weisskoff, R.H., "Ultra-fast Imaging," Magnetic ResonanceImaging 9, 1-37 (1991). Zur, Y., Wood, M., and Neuringer, L., "Spoilingof Transverse Magnetization in Steady State Sequences," MagneticResonance Medicine 21, 251-263 (1991)].

3. Real-time NMR imaging can provide information on the state of thetissue in and around the freezing interface such as the position of thefreezing interface, its velocity, the temperature distribution in theunfrozen region, and the temperature distribution in the unfrozenregion. The temperature distribution in the unfrozen region can befound, for example, from T1-weighted Inversion Recovery RapidAcquisition with Relaxation Enhancement (IR-RARE) sequences [Dickinson,R.J., Hall, A.S., Hind, A.J., Young, I.R., "Measurement of Changes inTissue Temperature using MR Imaging," Journal of Computer AssistedTomography, 1986:10; 468-472], and other techniques [Le Bihan, D.,Delannoy, J., Levin, R.L., "Temperature Mapping with MR imaging ofMolecular Diffusion: Application to Hyperthermia," Radiology1589:853-857], and [Rubinsky, B., Gilbert, J.C., Onik, G.M., Roos, M.S.,Wong, S.T.S., Brennan, K.M., "Monitoring Cryosurgery in the Brain and inthe Prostate with Proton NMR," Cryobiology, April 1993], and thetemperature distribution in the frozen region can be calculated knowingthe position of the interface and the temperature of the probe as wasdone with ultrasound [Gilbert, J.C., Rubinsky, B., Onik, G.M.,"Solid-Liquid Interface Monitoring with Ultrasound During Cryosurgery,"ASME paper #85-WA/HT-83, 1985]. This information can be used to adjustand control the freezing process in situ, either by providinginformation to the surgeon or in an automated control system.

4. Post-cryosurgical MR follow-up provides a noninvasive means ofdetermining the efficacy of treatment. T2-weighted MRI can track theevolution of edema and other changes in and around the tissue treatedwith cryosurgery over periods of minutes to days [Vining, E., Duckwier,G., Udkoft, R., Rand, R., Lufkin, K., "Magnetic Resonance Imaging of theThalamus Following Cryothalamotony for Parkinson's Disease andDystonia," Journal of Neuroimaging, 1, 196-198 (1991); Rubinsky, B.,Gilbert, J.C., Onik, G.M., Roos, M.S., Wong, S.T.S., Brennan, K.M.,"Monitoring Cryosurgery in the Brain and in the Prostate with ProtonNMR," in print, Cryobiology, 1993]. T1-weighted MRI can detect bleedingand changes in the state of any post-cryosurgical hemorrhage. With theuse of contrast agents such as Gd-DTPA (gadopentetate dimeglumine),T1-weighted MRI can also delineate the region of blood-brain barrierdisruption after freezing as will be discussed below. Furthermore,spectroscopy and spectroscopic imaging of phosphorous, carbon, andsodium are also useful in determining the extent of tissue damage aftercryosurgery. In the case of sodium, it is the ratio between theintracellular to extracellular sodium which are indicative of damage. Inthe case of phosphorous, it is the molecular composition, and therelative composition in which the compound appears as, ATP, ADP,phosphocreatine or inorganic phosphorous which indicates the extent ofthe damage.

In summary, NMR imaging can be used in four differeilt stages duringcryosurgery to improve the results of the procedure: 1) in thepreoperative stage in a predictive mode to plan the procedure andoptimize the application of cryosurgery; 2) during cryosurgery to imagethe process of freezing; 3) for interactive control during the surgeryto control and optimize the application of cryosurgery; and 4) in thepost-operative stage to evaluate the damage induced by the procedure.

Despite the advantages of MRI, the efficient use of MRI with cryosurgeryis inhibited by the nature of the MRI apparatus and limitations of thetechnique. In particular:

1) MRI operates in a magnetic environment and employs radio frequencyelectromagnetic energy. Consequently conventional metallic cryosurgicalprobes cannot be used with MRI. Experiments reported by other groupswere limited to the use of a gauze immersed in liquid nitrogen and thenapplied to the skin [Isoda, H., "Sequential MRI and CT Monitoring inCryosurgery--an Experimental Study in Rats," Nippon Acta Radiologica,49:1499-1508, 1989 (in Japanese)], or to the use of a styrofoam cupfilled with liquid nitrogen [Matsumoto, R., Oshio, K., Jolesz, F.,"Monitoring of Laser and Freezing Induced Ablation in the Liver withT1--Weighted MR Imaging," Journal of Magnetic Resonance Imaging, 2,555-562, 1992]. The present invention relates to the design of acryosurgical probe compatible with MRI.

2) It is preferable for MR imaging that the region imaged be stationarywith respect to the magnet. The present invention is therefore astereotactic apparatus for positioning cryosurgical probes in relationto the MRI apparatus.

3) During cryosurgery the region of interest that is frozen and imagedis usually small relative to the whole region imaged by MRI. This isparticularly the case in dermatology where freezing penetrates only afew millimeters from the probe. The present invention is thereforedirected to a cryosurgical probe on which the radio frequency coil ofthe MRI system is attached. This generates a much higher signal to noiseratio in the region of interest, with a much higher resolution (of about100 μm). This is an optimal solution, since the cryosurgical probe isnaturally in the center of the region of interest. Another advantage ofmounting the coil on the probe is that it is then possible to constructa probe where the cryogen also cools the coils, thereby reducing thermalnoise and increasing the signal-to-noise ratio still further.

4) The low signal intensity of atomic species other than protons makesthe signal-to-noise ratio of these species (such as phosphorus orsodium) very low. Attaching a receiver coil tuned to these species tothe cryosurgical probe is advantageous since the signal/noise ratio issignificantly improved by analyzing only the area of interest.Furthermore the cryosurgical probe is by the nature of its function inthe center of the region of interest.

Attaching the MR receiving coil to the cryosurgical probe provides theadvantages of increased resolution in the area of interest duringcryosurgery, and increased ability to determine the effectiveness ofcryosurgery, without the need for introducing additional devices in thepatient. Such an arrangement may also be useful with other microsurgicaltechniques, such as laser surgery, or mechanical resection.

The advantage of an MRI assisted microsurgical system is that it canprovide a better resolution in the region treated by various surgicaltechniques and it can be used to better monitor tissues during surgery.Furthermore, since it involves only the attachment of small electriccomponents to the surgical device, it does not substantially increasethe bulk of the device. This technique can remove the need for opticalimaging of surgical procedures using fiber optics, thereby facilitatingsurgery with smaller devices and in smaller areas.

The present invention relates generally to methods and apparatus forimproving the results of cryosurgery, and more particularly to methodsand apparatus for improving the results of cryosurgery usingpreoperative surgical optimization planning, real-time NMR imagingduring surgery, control of the cryosurgical procedure using NMR imageinformation, and/or post-operative NMR monitoring of cryodamage.

An object of the present invention is to provide methods and apparatusfor improving cryosurgical results.

Another object of the present invention is to provide methods andapparatus for improving cryosurgical results using preoperative surgicalplanning in combination with MR image information.

Another object of the present invention is to provide methods andapparatus for improving surgical results, particularly cryosurgicalresults, using real-time NMR imaging during surgery.

Another object of the present invention is to provide methods andapparatus for improving cryosurgical results by controlling thecryosurgical procedure using real-time NMR image information.

Another object of the present invention is to provide methods andapparatus for postoperative NMR monitoring of cryodamage.

,Another object of the present invention is to provide methods andapparatus for utilizing the heat and mass transfer equations in thepreoperative planning stage and during surgery to improve cryosurgicalresults.

Another object of the present invention is to provide methods andapparatus for determining tissue temperatures using NMR data to improvecryosurgical results.

Another object of the present invention is to provide methods andapparatus for determining tissue temperatures by solving the heat andmass transfer equations in the frozen region.

Another object of the present invention is to provide methods andapparatus for improving cryosurgical results using an MR compatiblecryoprobe and stereotactic device.

Another object of the present invention is to provide methods andapparatus for improving cryosurgical results by increasing theresolution of MR monitoring using an MR coil mounted on the cryoprobe.

Another object of the present invention is to provide methods andapparatus for evaluating cryosurgical results using NMR spectroscopy andimaging, such as phosphorous-31 or sodium-23 spectroscopy and imaging.

Additional objects and advantages of the invention will be set forth inthe description which follows, and in part will be obvious from thedescription, or may be learned by practice of the invention. The objectsand advantages of the invention may be realized and obtained by means ofthe instrumentalities and combinations particularly pointed out in theclaims.

SUMMARY OF THE INVENTION

The present invention is directed to methods and apparatus for real-timeinteractive cryosurgery utilizing information obtained from magneticresonance imaging.

The present invention is directed to a stereotactic system for magneticresonance monitoring of cryosurgery which includes a frame which istransparent to magnetic resonance imaging, a cryoprobe compatible withMRI, a means for positioning the cryoprobe relative to the frame, andmagnetic resonance visible markers for orientation and positioningpurposes.

The present invention is also directed to methods for monitoring damageto a biological tissue using sodium-23 spectroscopic imaging, orphosphorus-31 spectroscopic imaging and detecting changes in PCr,inorganic phosphorous, or ATP levels.

The present invention is also directed to a cryoprobe which has a radiofrequency magnetic resonance coil mounted at the intracorporeal endthereof, thereby providing an increased signal-to-noise ratio.

The present invention is also directed to a method for monitoringtemperatures of a freezing region in a biological tissue with protonmagnetic resonance imaging. The method consists of correlating theregion which generates no proton resonance signal with the frozen partof the freezing region, solving the heat equation in the frozen partutilizing the known temperatures at the boundaries, and determiningtemperatures in the unfrozen part by calculations based on measured T1times.

BRIEF DESCRIPTION OF THE DRAWING

The accompanying drawings, which are incorporated in and constitute apart of the specification, schematically illustrate a preferredembodiment of the invention and, together with the general descriptiongiven above and the detailed description of the preferred embodimentgiven below, serve to explain the principles of the invention.

FIG. 1 shows an embodiment of the stereotactic cryosurgical probe systemof the present invention.

FIG. 2 is a cut-away view of the stereotactic probe system of FIG. 1 inthe bore of an magnetic resonance imaging magnet.

FIGS. 3a-e show view of a rabbit brain prior to (a), during (b and c)and after cryosurgery (d and e). FIG. 3f shows a histological section ofthe brain for comparison.

FIGS. 4a, 4b and 4c show cross-sectional, magnified, and end views,respectively, of a surface cryoprobe according to the present invention.

FIGS. 5a and 5b show the circuitry of the proton and spectroscopy coils,respectively, of the surface cryoprobe shown in FIGS. 4a, 4b and 4c.

FIGS. 6a and 6b show cross-sectional side and end views, respectively,of a prostate cryosurgical probe according to the present invention.

FIGS. 7a shows a magnetic resonance image of the abdomen of a dog. Theprostate, visible in the central square in FIG. 7a, is shown magnifiedin FIGS. 7b through 7g during freezing and thawing of a lobe of theprostate.

FIG. 8a shows a histological section of the prostate shown in FIGS.7a-7g. FIG. 8b is a magnified view of the boundary of the cryolesion.

FIG. 9 provides experimental data correlating magnetic resonance signalintensity versus temperature.

FIG. 10a plots signal intensity versus position at two times during thepropagation of a freezing interface across a sample.

FIG. 10b shows a comparison between theoretical and experimental data oftemperature versus position in the unfrozen region during freezing.

FIGS. 11a through 11r show a time sequence of images of a freezinginterface propagating through a gel taken with a surface cryoprobe ofthe present invention.

FIGS. 12a through 12d show a time sequence of images of a cryolesion ona rabbit leg taken with a surface cryoprobe of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will be described in terms of the preferredembodiment. The preferred embodiment is an apparatus and method formagnetic resonance imaging assisted cryosurgery.

One of the major problems faced by cryosurgeons is the inability toevaluate the effectiveness of the treatment immediately. However, NMRprovides the ability to perform such evaluation through phosphorous-31(³¹ p) and sodium-23 (²³ Na) spectroscopic imaging to asses cell damageproduced by freezing. Although other nuclei can be also seen with NMRand may be also useful for monitoring damage, sodium-23 andphosphorous-31 are physiologically significant and because of theirnatural abundance they are easily detected by NMR. Spatial resolution inspectroscopic imaging experiments can be on the order of 1 cm for ³¹ pand 0.5 cm for ²³ Na for a signal-to-noise ratio of 10 in a 30 minacquisition time. Spectra acquired with implanted receiver coils or withcoils on the cryosurgical probe require substantially reducedacquisition times.

The following changes are observed in tissue following thawing:

1) A decrease in PCr (phosphocreative) and ATP (adenosine triphosphate)and increase in inorganic phosphorous (Pi) lines in proportion to thefraction of damaged cells.

2) An increase in the total ²³ Na signal due to cell membrane disruptionand edema, since the amount of intracellular sodium is less than that ofextracellular sodium. If the cell membrane is broken, sodium brought bythe blood supply can also fill the space occupied by the cells. Thechanges in the ²³ Na signal are most easily observed in the brainbecause of the small size of the extracellular volume in normal tissue(where the ²³ Na concentration is high).

Preoperative planning

Conventionally, cryosurgery is performed using a single cryosurgicalprobe. The surgeon would introduce the probe in the approximate centerof the tissue to be destroyed and the freezing would proceed until, tothe best estimate of the surgeon, the tumor or tissue to be destroyedhas been frozen completely.

The ability to image the process of freezing in real time using variousmeans such as ultrasound, has resulted in more precision and theapplication of cryosurgery to more complex situations. Irregularlyshaped tissues, such as the prostate, can be frozen using multiplecryosurgical probes to achieve an irregularly shaped frozen region.During a typical cryosurgical procedure performed with imaging, theprobes can be placed accurately by the surgeon and the extent of thefrozen region can be monitored accurately.

Despite the fact that the probes can be accurately placed and the extentof freezing can be observed[, the criteria for the actual probeplacement has not changed since the pre-imaging period. The placement ofthe probes is still informed by experience and based on an estimate ofhow the freezing interface will develop. While in the past lack ofaccuracy in placement and in freezing would not affect the overallresults of this procedure, which was inaccurate by itself, with imagingthe placement of the probes becomes one of the main sources ofinaccuracy in cryosurgical treatment. The probes must be accuratelyplaced prior to freezing since once the freezing process has begun it isimpossible to remove the probes from the tissues.

Pretreatment planning is important since it can provide the cryosurgeonwith valuable information on the placement of multiple cryosurgicalprobes, and the design of freezing protocols. Multiple cryoprobes areuseful for freezing several sites simultaneously, regions too large tobe frozen by a single cryoprobe, or unusually shaped regions. Generally,surgeons have difficulty in planning surgical procedures using multipleprobes because of the large number of variables that must be calculatedsimultaneously. Providing the surgeon with an estimate of theperformance of a particular cryosurgical protocol in the planning stage,will allow pretreatment evaluation of alternate plans. Treatmentplanning is also important because cryosurgical probes may not be movedonce freezing starts. Thawing, repositioning the probes, and refreezingafter thawing is time-consuming, so it is important to achieve the mosttissue destruction in the target region with a minimum of freezingepisodes.

In the pretreatment planning stage, anatomical information of the targetregion in a specific tissue obtained from NMR images or other imagingtechniques is incorporated into the mathematical model to provideguidelines for selecting the number of cryosurgical probes, and thetypes, :sizes, placement, and paths of introduction of the probes.Planning a cryosurgical procedure involves the following steps:

1) Identifying a target region to be frozen, and any adjacent criticalanatomy that must be protected from freezing.

2) Estimating the heat transfer properties of the tissue, based onfactors such as the thermal conductivity of the tissue and the locationsof any local heat sources such as blood vessels.

3) Running an optimization program to determine the number, type, andsize of the cryosurgical probes, together with the optimal path ofinsertion and the required thermal protocol.

Identification of the target region is accomplished using multi-slice orthree-dimensional NMR datasets much as it is done in radiotherapy. Theimaging technique is selected to yield good tissue contrast between thetumor to be treated and the surrounding tissue. For instance,multi-slice spin echo (TE=33/100 ms, TR=2000 ms) or 3-D spoiledsequences are preferred techniques for gathering anatomical information.In each slice, the target region is identified by automated or manualregion drawing, and the bounding surface constructed by tiling betweenslices. In addition, any thermally or structurally important structuresare identified as regions of interest. Coordinates of all significantstructure in the target region and vicinity and is stored in thecomputer together with the relevant thermal properties of the tissue foruse in developing the treatment plan. A velocity compensatedthree-dimensional FLASH technique is employed. in which blood flowinginto the region appears bright. Slabs of three-dimensional slices areoriented to obtain maximum contrast from inflowing blood. Vessels areidentified by adjusting the contrast for maximum visibility(thresholding), and a vascular tree for the volume of interest is storedin the computer. Because we consider small volumes with only a few largevessels, tracking vessels from slice to slice is not difficult and maybe done by hand if necessary. The vasculature in the target volume isused in the heat transfer model.

After the region to be treated and the surrounding tissues are culled byNMR, the thermal characteristics of the tissues are identified from atissue library. The region to be destroyed is identified together withinadmissible paths for probe penetration and other operationconstraints. Then, the optimization program is run to provide thesurgeons with the required information concerning the number and typesof probes, the path of insertion, and the required temperature on thecryosurgical probes. This technique using a downhill simplexoptimization procedure is described in detail in Keanini, R., Rubinsky,B., "Simulation and Optimization of Three- Dimensional Multi-ProbeProstatic Cryosurgery," J. Heat Transfer--ASME Trans, 114, 796-801,1992, and is incorporated herein by reference.

Stereotactic cryosurgery system

Despite the obvious advantages of using NMR with cryosurgery there arealso drawbacks. In particular, access into an NMR apparatus is limited.Therefore, NMR monitoring of cryosurgery requires special preparations.The stereotactic apparatus of the present invention facilitatespositioning of the cryosurgical probes within the tissue, relative tothe NMR device and the patient. The device must be made mostly withmaterials that do not disrupt NMR signals,, but and must also containsome materials that are visible with NMR when those materials located atknown positions relative to the cryosurgical probe(s). For example,fastening devices for the probes can be marked with materials visibleunder NMR. The device must also contain a means of attachment to thepatient at known positions and to the NMR apparatus at predeterminedpositions. In a typical procedure the probe positioning device isattached to the patient and positioned at a predetermined positionwithin the NMR magnet so that the tissue to be treated is optimallyvisible with NMR and the specific NMR visible sites on the attachmentdevice are also visible under NMR monitoring. The path is evaluatedeither by the surgeon or using the preplanning computer programsdescribed earlier. If needed, the positioning device is moved relativeto the patient and the NMR machine until an optimal path can beachieved.

An embodiment of the magnetic resonance imaging compatible stereotacticholder 300 of the present invention is shown in FIG. 1. The stereotacticholder 300 is particularly adapted for holding a small mammal, such as arabbit, for cryosurgery of the brain. Other embodiments suited forcryosurgery of other body parts of other animals may also be constructedand are also within the scope of the present invention. The stereotacticholder 300 is constructed from clear plexiglass plates havingthicknesses of 1/4 and 3/16 inches, and nylon screws. Most nylon screwswhich secure the plexiglass plates are omitted from FIG. 1 for clarity.No metal parts are used in the construction of the stereotactic holder300.

The holder 300 consists of a positioning plate 310, and an operationssection 320 attached to the positioning plate 310. Left and rightcalibration scales 312l and 312r are provided along the side edges ofthe positioning plate 310 for the purpose of gauging the longitudinallocation of the holder 300 inside the magnet 400, as shown in FIG. 2.The positioning plate 310 has a width of approximately 21 cm. Theoperations section 320 has a base plate 325 with left and right flangededges 327l and 327r, respectively. (Components of the same typepositioned on the left and right sides of the stereotactic holder 300will be given reference numerals appended with the letters "l" and "r"to denote the left and right components, respectively. Similarly, frontand back components of the same type will be given reference numeralsappended with the letters "f" and "b" respectively. When left and right,and/or front and back components are referred to collectively, thereference numeral will not be appended with a letter.) The base plate325 has a width of approximately 10 cm.

Attached to the flanged edges 327l and 327r adjacent the positioningplate 310 are left and right shoulder plates 330l and 330r,respectively. Attached to the flanged edges 327l and 327r adjacent theshoulder plates 330 are left and right positioning plates 340l and 340r,respectively. The shoulder plates 330 and the positioning plates 340have a height of approximately 8 cm. The right adjustment plate 340r hasa front vertical slot 345rf and a rear vertical slot 345rb. Similarly,left adjustment plate 340l has two vertical slots 345l. A U-shaped probebracket 350 is mounted on top of the adjustment plates 340 by four pairsof nylon adjustment screws 355, one pair extending through each verticalslot 345 to screw holes (not shown) in the bracket 350. By screwing theadjustment screws 355 into the probe bracket 350, the force between theheads of the adjustment screws 355, the adjustment plates 340, and thevertical sections of the probe bracket 350 immobilizes the probebracket. A stereotactic holder probe 370 is mounted in the midsection ofthe probe bracket 350.

As shown in FIG. 1, and the cross-sectional view of FIG. 2, a liquidnitrogen inlet tube 372 and a liquid nitrogen outlet tube 374 extendfrom the body 376 of the probe 370. The inlet tube 372 and the outlettube 374 are mounted 60° apart, as shown in FIG.1. (The inlet and outlettubes 372 and 374 are shown mounted 180° apart in FIG. 2 for clarity.)The inlet tube 372 is L-shaped. The inlet and outlet tubes 372 and 374are mounted on the body 376 near the upper end of the body 376 so thatthere is clearance between the upper end of the body 376 and the magnetbore while still maintaining structural integrity. The body 376 isapproximately 4 cm high, and has a width of approximately 1.5 cm. Thebody 376 of the probe 370, and the inlet and outlet tubes 372 and 374are made of Pyrex glass. The lower section of the probe 370 is a conicalsection, the lower tip being circular with a width of approximately 0.7cm.

The inlet tube 372 is connected via silicone rubber tubing (not shown)to a liquid nitrogen dewar (not shown). The flow rate of the liquidnitrogen is monitored by observing the state of the nitrogen leaving theexhaust outlet 374. When the exhaust is in the ]Liquid state the flowrate is greater than necessary to produce the minimum possibletemperature at the tip of the probe 370. The bottom end of the inlettube 372 is adjacent the bottom of the probe body 376 (approximately 0.6cm above the bottom surface) so that the liquid is delivered directly tothe tip of the probe 370. The exhaust outlet 374 is also connected tosilicone rubber tubing (not shown) to channel the exhaust gases awayfrom the subject so as not to cause cooling or freezing of regions ofthe subject other than those in direct contact with the tip of the probe370.

FIG. 2 is a front view of the stereotactic holder 300 positioned insidethe cylindrical interior cavity 410 of a magnet 400 such as the Bruker2.35 Tesla magnet owned by Lawrence Berkeley Laboratories, combined witha cut-away view of the probe 370. The positioning plate 310 has a knownwidth, and therefore the height of the components of the holder 300,such as the probe 500 and the head screws 360, are also known. The widthof the positioning plate 310 is chosen such that the holder 300 isoptimally positioned to minimize gradients in the magnetic fieldgenerated by the magnet 400. The graduations of the calibration scale312 along the side edge of positioning plate 310 provide a measurementof the distance between the probe 370 and the end of the magnet 400. Theposition of the probe 370 along the longitudinal axis of the cavity 410is determined by noting the numerical value of the first graduationwhich extends past the end of the magnet 400.

To use the stereotactic holder 300 for MRI assisted cryosurgery of arabbit, the rabbit (not shown) is placed supine on the holder 300 withits head positioned between the head screws 360, its shoulders betweenshoulder plates 330, and its rear quarters resting on the positioningplate 310. The position of the head is stabilized by adjusting headscrews 360 so as to produce a light pressure on the skull. The cryoprobe370 is brought into contact with the surgical area by verticaladjustment of the probe bracket 350. The cryoprobe 370 is repositionedby loosening the adjustment screws 355, positioning the bracket 350, andretightening the adjustment screws 355.

Cryosurgical experiments were peformed on an adult New Zealand rabbitweighing 3-4 kg. The experiments were conducted under approved LBLAnimal Welfare Research Committee protocols. These experiments aredescribed in detail in Gilbert, J.C., Rubinsky, B., Roos, M.S., Wong,S.T.S., and Brennan, K.M., "MRI-Monitored Cryosurgery in the RabbitBrain," Magnetic Resonance Imaging, submitted January 1993, and isincorporated herein by reference. The rabbit was anesthetized with anI.M. (intra muscular) injection of ketamine (30 mg/kg), rompun (3mg/kg), and acepromazine (0.6 mg/kg), and additional doses of anesthesiawere administered as necessary by I.M. The rabbit was immobilized in thestereotactic holder 300 with the cryoprobe 370 held against the skull,approximately 1 cm caudally from the eye sockets over the centralportion of the cerebral cortex. The entire rabbit/cryoprobe/frameassembly was then placed in the magnet bore 410 with the brain locatedin the center of the magnet 400. Sagittal scout images were acquired(spin-echo; TE=33 ms; TR=400 ms) with a drop of water in the tip of aPyrex cryoprobe 370 to determine the appropriate freezing location, inthis case being the midline center of the surface of the cerebralcortex. The assembly was then removed from the magnet bore 410, thecryoprobe 370 was removed, and a 5 mm diameter hole was made in theskull the appropriate distance from the aforementioned drop of waterusing a dentist's drill, taking care not to breech the dura. Thecryoprobe 370 was replaced in the holder 300 with the tip just touchingthe surface of the brain. The rabbit/cryoprobe/frame assembly was thenput back in the magnet bore in the same location as before. FIG. 3ashows an MRI view of the rabbit brain prior to freezing. The aperture705 in the skull 700 is visible. The probe 370 is located in theaperture 705 but is not visible since it is constructed of materialstransparent to proton NMR.

Baseline images were acquired before freezing in six coronal planes (3mm thick, 1 mm apart) covering most of the volume of the brain. Becausepulse sequences for monitoring freezing were continued throughout therabbit experiments, baseline images were acquired using several pulsesequences. In particular the pulse sequences were: spin-echo (TE=33/100ms; TR=2 sec; total acquisition time 12.8 min); T1-weighted spin-echo(TE=28 ms; TR=400 ms; total acquisition time 2.5 min); and radiofrequency spoiled gradient echo (TE=14 ms; TR=50 ms; total acquisitiontime 14 seconds/slice). Radio frequency spoiled gradient echo pulsesequences (TE=14 ms; TR=50 ms) with and without Gd-DTPA is the preferredpulse sequence since it provides good time resolution with adequatesignal to noise ratio. T1-weighted spin echo sequences have also beenused.

The total acquisition time for an image using radio frequency spoiledgradient echo pulse sequence can be less than 15 seconds. Total time forprocessing and display is less than 5 seconds under typical network andmachine loads. Thus 20 seconds is required to acquire and reconstructthe first slice, and subsequent slices appear every 15 seconds.

Imaging began simultaneously with the opening of the valve on a liquidnitrogen dewar and continued throughout the freeze/thaw cycle. Freezingwas conducted for approximately 10 minutes until a freezing interface710 had progressed approximately 5 mm ventrally into the cerebral cortexas shown in FIG. 3b. This usually occurred after approximately 5 minutesof freezing. Thawing was usually complete within eight minutes after theflow of liquid nitrogen was stopped. After thawing was complete, imageswere acquired for up to an additional four hours.

Before freezing the rabbit brain appeared normal and major anatomicalstructures, such as the cerebral cortex, hippocampus, and thalamus, arevisible in the spin-echo images. Although less anatomical detail isavailable from the radio frequency spoiled gradient echo images, theseimages have adequate spatial resolution and superior time resolution forlocating the position of the freezing interface. As shown in FIGS. 3band 3c, during freezing the boundary 710 between the frozen and unfrozentissue is a clearly visible circular arc. The dark region 715 in FIG. 3ccorresponds to the semicircular section of the bilateral frozen lesionencompassing the cingulate cortex and part of the hippocampus.

In the preferred postcryosurgical follow-up the rabbit is imagedperiodically for up to four hours after freezing using spin-echo pulsesequences (TE=33/100 ms; TR=2 s) without Gadolinium DTPA. As shown inFIG. 3d, five minutes after thawing is complete the previously frozenregion is again visible. There are some contrast changes observable inthe region of necrosis. For instance, the development of edema over thefour-hour follow-up period is visible using T2-weighted spin-echoimaging. As shown in FIG. 3e, during this period a bright ring 720corresponding to the freezing boundary is observed to increase in signalintensity. (In FIG. 3e the outline 725 of the probe 370 is also visibledue to condensation on its outer surface.) However, the central portionof the lesion is darker than the boundary 720, probably because there isgreater destruction of the vasculature there

The brain section shown in FIG. 3f is a coronal slice through thedorsomedial nucleus of the thalamus. There is good correlation betweenthe right side of the coronal brain section and the NMR images acquiredduring the experimental procedure. The coronal section is embedded inparaffin, sectioned and stained with hematoxylin and eosin usingstandard histologic techniques. Grossly, the brain has a roughlycircular, symmetrical 17 mm (diameter) reddish brown hemorrhagic andnecrotic area in the superficial dorsal cerebral cortex 726 that matchesthe area of the freezing lesion. This lesion is a pale, edematous ovalarea symmetric about the cingulate gyrus 727, 17 mm in diameter at thesuperior surface and extending 7 mm ventrally near to the dorsal surfaceof the thalamus. The central part of the lesion is hemorrhagic.

The lesion and its T2-weighted NMR image can be seen to correspondclosely. These results indicate that NMR imaging may be an accurateestimator of damage in postcryosurgical follow-up in addition to itsrole in monitoring the freezing process during cryosurgery.

The Surface Probe

Using conventional NMR monitoring techniques the images of larger organssuch as the brain provide adequate resolution. The image of smallerorgans, such as the skin, the prostate, or the blood vessels, willhowever suffer from poorer resolution. However, during cryosurgery ofthe skin or the prostate, a view of the whole body is not of interest,whereas better dietails of the prostate are highly desirable. During MRimaging, the radio frequency coil usually surrounds the whole body andreceives signal from the whole body, while the region of interest isonly in the near vicinity of the surgical probe. Therefore, if RF coilsare located only in the vicinity of the region of interest, theresolution of the MR image is much better since the signal to noiseratio is higher. If one images the whole body, but is interested only indetails in a small portion of the body (the signal), the noise is stillgenerated from the whole area imaged (the body) and the signal to noiseratio is poor. Conversely, if the RF coil images only the region inwhich surgery is performed, then the signal and the noise come fromroughly the same area, and the resolution becomes much better. This isparticularly important with low intensity signals, such as those from ¹³C ²³ Na and ³¹ p. In the present invention the surgical probe itselfserves as a chassis on which the RF coils are mounted.

An RF coil acts as an antenna which picks up radio frequency signals.The coil is part of an electrical circuit designed to resonate in therange of frequencies of interest. The coil may have a variety ofconfigurations such as, but not limited, to surface coils, Helmholzcoils and solenoid coils [Hurst, G.G., Hua Jiannin, Duerk, J.L., Cohen,A.M., Intravascular (Catheter) NMR Receiver Probe: "Preliminary DesignAnalysis and Application to Canine Iliofemoral Imaging," MagneticResonance in Medicine 24, 343-357 (1992); Zemtsov, A., et al., "MagneticResonance Imaging of Cutaneous Neoplasms: ClinicopathologicCorrelation," Journal of Dermatological Surgery and Oncology,1991;17:416-22; Zemtsov, A., et al., "Magnetic Resonance Imaging ofCutaneous Melanocytic Lesions," Journal of Dermatological Surgery andOncology, 1989; 15:854-58].

The surface probe 500 of the present invention having integrated RF coilis shown in cross-section in FIG. 4a. The probe 500 is comprised of acylindrical body 510 made of cast acrylic. The body 510 has a centralcylindrical boiling chamber 520, and a delivery passage 525 and fourexit passages 530 extending from the boiling chamber 520 to the rear ofthe body 510. As can be seen in the rear view of the probe 500 of FIG.4c, the four exit passages 530 are evenly spaced around the deliverypassage 525. The end of the boiling chamber 520 opposite the deliverypassage 525, henceforth to be termed the front end, is sealed with acylindrical piece of quartz 540, and there are three thin circularpieces of boron nitride loaded silicone 545b, 545c and 545f (referred tocollectively by reference numeral 545) in contact with the front face ofthe quartz 540, as shown in the magnified view of FIG. 4b. Locatedbetween the central silicone disk 545c and front silicone disk 545f is afirst spectroscopy coil 555a, and located between the central siliconedisk 545c and the rear silicone disk 545b is a second spectroscopy coil555b. The two coils 555 are electrically connected to provide a doublecoil configuration. The spectroscopy coils 555a and 555b are made of0.005 inch thick copper foil, and have a diameter of 0.6 inches and awidth of 0.1 inch. The quartz 540, silicon disks 545, and coils 555 areheld in place by an acrylic cap 560 which is secured to the acrylic body510 by four nylon screws 565 which are evenly spaced about theperimeter. The quartz 540 is thermally insulated from the acrylic body510 by a polystyrene insulation layer 562.

A single turn proton coil 535 is mounted to a coil mount 570 whichlaterally extends from the outside of the acrylic body 510. The protoncoil 535 has an outer diameter of 2.8 inches, an inner diameter of 1.8inches, and is made of 0.005 inch thick copper foil.

The circuitry of the probe 500 is shown in FIGS. 5a and 5b. As shown inFIG. 5a, the proton coil 535 is connected in series to a capacitor C3having a capacitance of 36pf and an inductor L2 having an inductance of45nH. The series combination of the proton coil 535, the capacitor C3,and the inductor L2 are connected in parallel to a capacitor C1 having acapacitance of 152pf, and a tunable capacitor C2. The input to thissystem is grounded on one side and connected to a tunable capacitor C4on the other side.

As shown in FIG. 5b, the spectroscopy coil 555 is connected in parallelto a capacitor C7 having a capacitance of 91pf and a tunable capacitorC6. One side of this circuitry is connected to ground and the other sideis connected to a tunable capacitor C5. The spectroscopy coil circuitryis tunable to the magnetic resonance frequencies phosphorous-31 orsodium-23. By changing the value of C7, the spectroscopy coil circuitmay be also tunable for ¹³ C or ²³ Na nuclei.

The cryoprobe 500 is designed to achieve a uniform temperature profileacross the probe surface near the specimen, and to provide optimalimaging. A uniform radial temperature distribution is desired so thatthe freeze zone in the specimen has a flat ice front in the region to beinvestigated. The effective thermal resistance between the boilingchamber 520 and the front probe surface is kept low in order to attainhigh freeze rates. The probe 500 is designed to give a highsignal-to-noise ratio, and to pick up FID's, free induction delays orjust NMR signals,, from a relatively well defined geometric area.Clearly, all construction materials must be suitable for use in a highmagnetic field, and are preferably electrically nonconductive.

Uneven liquid nitrogen boiling over a surface such as the front of theboiling chamber 520 creates high thermal gradients on the boilingsurface. The quartz ! 540 at the front of the chamber, together with thepolystyrene insulation 562 located between the quartz 540 and theacrylic body 510 provide a system which has a uniform and large thermalgradient only in the .axial direction across the quartz 540 and silicone545. The boron nitride loaded silicone 545 provides a high thermalconductivity matrix for the spectroscopy coil 555. Furthermore, underpressure, the boron nitride loaded silicone 545 offers low thermalcontact resistance between both the quartz 520 and the acrylic bodyencasement 510, lowering the overall thermal resistance of the device inthe axial direction.

The probe 500 is constructed such that contact pressure between thequartz 540 and the silicone 545, and between the silicone 545 and theouter encasement 510 is increased as the probe 500 cools. Since thecoefficient of thermal expansion of the acrylic body 510 is much largerthan that of the quartz 540, cooling of the entire probe 500 causes thesilicone 545 to be squeezed slightly. This pressure is required toensure a consistent total thermal resistance throughout the coolingperiod.

It is well known that the region for which a surface coil is effectiveas a probe extends approximately one surface coil radius away from theplane of the coil. There is no definite cut-off and the extent of theregion may be altered to some degree by control of the pulse widths, butto first order the range of a coil is set by the effective magneticfield. Thus, with no special encoding the probe 500 will receive signalsfrom a region roughly approximated by a hemisphere whose great circlelies on the coil plane 555 or 535. Surface coils are especially usefulfor spectroscopy studies of tissue near a surface because thesignal-to-noise ratio is high because of the highly localized magneticfield from the coil. The coil 555 is placed as close as physicallypractical to the tissue, and its diameter is chosen such that the signalreceived by the probe lies primarily in the region under investigation.The spectroscopy coil 555 has been configured for 31p (2.4 T) using astandard tuning circuit. The coil 555 may be tuned for use with ³¹ C, ²³Na, and ¹⁹ F by simply changing capacitor values. A dual-turnspectroscopy coil 555 is used in this case because the inductance of asingle turn coil is too small to easily match with available standardcapacitors.

The size and position of the proton coil 535 have been chosen so thatthe entire extent of the frozen region can be imaged. The same surfaceprobe principles mentioned above apply here, though the problem ofsignal-to-noise is clearly not as important for the proton coil as forthe spectroscopic coils since the abundance of protons is much greaterthan that of phosphorous-31 or sodium-23 atoms.

FIGS. 11a through 11r show a time sequence of radio frequency spoiledgradient echo images taken with the surface probe 500 of the presentinvention in contact with the surface of a 50 millimolar H₃ PO₄ gelatin.In each image it takes about 25 seconds to acquire and process the data.The dark circle clearly visible in FIGS. 11a through 11k is a rod crosssection having a diameter of 2.5 mm. The bead is 4 mm from the surfaceof the gelatin which appears as the dark border to the left of the imagein FIG. 11a. FIGS. 11a through 11r show the gel 0, 31, 61, 91, 121, 151,181, 215, 252, 285, 313, 348, 373, 404, 461, 501, 536, and 570 seconds,respectively, after the initiation of the flow of cryogen. The positionof the dark left hand border in FIGS. 11g and 11h clearly begins toadvance towards the rod, and after 4 minutes and 45 seconds, as shown inFIG. 11j, the interface appears to contact the rod. After 5 minutes 35seconds the flow of cryogen was discontinued, but as evidenced by FIGS.11l through 11o the interface continues to propagate.

The usefulness of the probe 500 in the treatment of skin cancer isdemonstrated by generating a cryolesion on the femur of a rabbit. Theprobe 500 was placed in contact with an ex vivo (approximately 30 hrsold) rabbit leg on the upper half of the femur and placed in a 2.4 T(100 MHz) small bore NMR. After electronic shimming on the sample,baseline T1 weighted 200 μm×200 μm resolution images were taken (TR 30ms, TE1 14.3 ms). Coolant was then turned on, and a series oftwo-dimensional spoiled gradient echo images were taken during thefreezing process.

FIGS. 12a-12d show a 5.12 cm×5.12 cm field of view of the rabbit leg850. In FIG. 12a the flow of liquid nitrogen has just begun and nofreezing interface is visible. In FIG. 12b the flow of liquid nitrogenhas been shut off after 7 minutes and 21 seconds, the frozen region 852emits no signal and is therefore dark, and the freezing interface 855 isapproximately a circular arc. FIG. 12c shows the rabbit leg 850 thirteenminutes and 43 seconds after the flow of liquid nitrogen was initiated.At this time the freezing interface 855 has propagated to a maximumdistance within the leg 850. FIG. 12d shows the rabbit leg 850twenty-six minutes and thirteen seconds after the flow of liquidnitrogen was first initiated. At this point the previously frozen region852 has just completed thawing.

This particular configuration of probe and surface coil shows good imageuniformity and sufficient signal-to-noise as far as 10 mm from thebottom of the probe surface when using fast spinecho sequences. The 58mm diameter surface coil provides sufficient image uniformity across the53 mm field of view, but diminishes significantly outside of this.Alternatively, larger coils may be used for increased depth penetrationand lateral extent, but the signal-to-noise sacrificed will at somepoint will be of an extent that 160 ms TR spin echo images are no longerfeasible.

All of the techniques for determining the precise location of theboundary between tissue and cryolesion during cutaneous cryosurgery haveto date depended on a significant amount of best guess judgement andexperience of the surgeon. However, the extent of the region may bechanged by any one of several factors including local areas of fatinside the region, increased blood flow caused by the induced coldinjury near the cryo lesion, and other factors including the proximityof nearby blood vessels which reduce the interface velocity near theirlocation. The most common method of instrumentation is the needlemounted thermocouple, but even this has the disadvantage of givingtemperature in only point locations; the actual lesion shape must beextrapolated from these measurements.

The probe 500 of the present invention is useful for cases where tumorsare particularly deep and/or malignant and so require extra care to becertain that the entire extent of the cancerous region has beencontained. In addition it is useful in areas around blood vessels whichcan change the expected pattern of the cryolesion.

Imaging of Prostate Surgery

To demonstrate the feasibility of magnetic resonance imaging forinternal surgery, prostate surgery has been performed on a dog. Theexperimental protocol is as follows: An adult male mongrel dog ispre-anesthetized with an intravenous injection of sodium thialmylal,intubated, and placed on a ventilator. Anesthesia is maintained usingmethoxyflurane (MOF/N₂ O/O₂) gasses and the body temperature ismonitored throughout the experiment in order to maintain the dog asphysiologically normal as possible. Imaging is conducted in a 1 meterdiameter, warm bore Oxford magnet with the dog secured in the supineposition. Prior to inserting the cryoprobe, sagittal and transversescout spin-echo images are acquired for slice localization.

Magnetic resonance imaging has the advantage of providing a real-timethree-dimensional view of the freezing process. Equipment associatedwith the technique must be compatible with large magnetic fields andradio frequency (RF) monitoring. In general, metallic cryosurgicalprobes are not compatible with large magnetic fields since most metalsare paramagnetic and would serve as an RF antenna and disturb thesignal. The cryoprobe of the present invention uses either a completelynonmetallic material such as Pyrex, or a metallic but nonmagneticmaterial such as brass or aluminum. In general., any existing probeconfiguration will also work with nonmetallic, or metallic butnonmagnetic or weakly magnetic compounds. The fact that long (30 cm)metallic probes (nonmagnetic) can work in the prostate increasessignificantly the range and possibilities of using cryosurgery with MRI.

The diameter cryoprobe used for the cryosurgical procedure is shown inthe cross-sectional side and end views of FIGS. 6a and 6b. Thecryosurgical probe 600 is 30 cm in length from the intracorporeal end602 to the extracorporeal end 604. It is constructed from threeconcentric brass tubes 610, 620 and 630, with outside diameters of0.159, 0.381, and 0.476 cm, respectively. Each tube 610, 620, and 630 is0.356 mm thick. The tubes 610, 620 and 630 are ungrounded to preventcurrents from flowing through the probe 600 in response to time-varyingmagnetic fields. The three tubes 610, 620 and 630 are heldconcentrically by small teflon spacers 606 placed in the gaps 615 and625 between the tubes 610, 620, and 630, as is shown in FIG. 6b. Theinner tube 610 is open ended at both ends. The middle tube 620 is closedat the intracorporeal end 602, and extends past the inner tube 610 atthe intracorporeal end. At the extracorporeal end of the probe 600 themiddle tube 620 is sealed to the inner tube 610 and the inner tube 610extends past the end of the middle tube 620. Liquid nitrogen is suppliedto the tip 602 of the cryoprobe 600 via a reducing "T" 670 at theextracorporeal end of the innermost tube 610. The vertical section ofthe reducing T 670 has an inner diameter of 0.63 cm. A gap 615 betweenthe innermost tube 610 and middle tube 620 allows for liquid and/orgaseous nitrogen to exhaust through an exhaust outlet 640 located 2 cmfrom the extracorporeal end 604 of the middle tube 620. The middle tube620 extends past the outer tube 630 at both the intracorporeal andextracorporeal ends, and the outer tube 630 is sealed to the middle tube620 at both ends. As shown in FIG. 6b (but omitted from FIG. 6a forclarity), sheets of insulating mylar 627 with thickness of 0.25 mil areplaced between spacers 606 in the gap 625 between the middle tube 620and the outer tube 630. The region 625 between the outermost tube 630and the middle tube 620 is then evacuated of gases through an evacuationtube, which becomes evacuation stub 650 when sealed, to increase thethermal insulation provided by the gap 625. The region of the middletube 620 past the extracorporeal end of the outer tube 630 isuninsulated and is therefore the active region 608 of the probe.Silicone rubber tubes convey liquid nitrogen from a dewar to the probe600, and from the exhaust outlet 40 to a locality away from the surgery.Connections to both the supply inlet and the exhaust outlet 640 are madevia using Swageloc™ connectors. It is important to note that thefunctionality of this probe illustrates that ungroundednon-ferromagnetic metals may be used to construct MRI compatible probes,even if the probe is quite long.

The cryoprobe 600 is inserted into the left lobe of the prostate using astandard surgical introducer-dilator technique under freehand controlbecause the symphysis pubis in the dog prevented use of a transperinealbiopsy guide. First, an NMR compatible 18-guage biopsy needle isinserted into the prostate and a floppy wire inserted through theneedle. The needle is then withdrawn and a small introducer is insertedover the wire. Successively larger introducers are inserted until onewhich can accommodate the 0.476 cm cryoprobe 600 is introduced. At eachappropriate stage, the correct positions of the introducer, dilator, andcryoprobe are verified using NMR images. Test using a variety of metalsshow that single small diameter (<0.5 cm) brass tubing produces asufficiently small magnetic susceptibility artifact in the NMR imagesthat cryoprobes constructed from this material can be used in the NMRmagnet without substantial degradation of the images.

Once the cryoprobe 600 is in position, baseline T₁ - and T₂ -weightedimages are acquired using spin-echo pulse sequences (T₁ -wtd: TE₁ =33ms, TR=200 ms; T₂ -wtd: TE₁ =331100 ms, TR=2000 ms). Imaging of thefreeze/thaw cycle begins simultaneously with liquid nitrogen flow andcontinues throughout the freeze/thaw cycle. A sufficiently high liquidnitrogen flow is maintained through the probe 600 that liquid nitrogendrips continually from the exhaust line, thus insuring the lowestpossible temperature of the active region 608 of the probe 600. A singlefreeze/thaw cycle is induced with the freezing portion lastingapproximately 7 minutes, and the thawing portion lasting approximately 8minutes. T₁ -weighted images are acquired approximately every 1.1minutes. When the images indicate that the right lobe of the prostatewas frozen (7 minutes of freezing) liquid nitrogen flow is stopped andthe prostate is allowed to thaw. After thawing, a final set of imagesare acquired, and the prostate excised and fixed in a 10% bufferedformalin solution for later histologic analysis.

FIGS. 7a through 7g shows a time sequence of images acquired during theprostate cryosurgery. FIG. 7a shows a T₁ -weighted spin-echo transversesection of the dog abdomen. The cryoprobe 600, inserted in the left lobe804 of the prostate 800 slightly lateral to the center of the lobe, isvisible. (In FIGS. 7a-7g, left and right is reversed.) The prostate 800in the square region in the center of FIG. 7a is shown magnified inFIGS. 7b through 7g. The prostate in the 23 kg dog is approximately 1.8cm in width and 2.5 cm in length, and is easily located in the NMRimages. FIGS. 7b, c and 7d show the prostate 800 before freezing isinitiated, 3 minutes after freezing has been initiated, and 7 minutesafter freezing has been initiated, respectively. After 7 minutes offreezing, the cryolesion, visible as a large dark region, encompassedmost of the left lobe 804 and extends 1-2 mm into the fatty tissuesurrounding the prostate 800. FIGS. 7e, 7f and 7g show the prostate 3minutes, 15 minutes and 30 minutes, respectively, after thawing begins.The thawing is complete after approximately 9.5 min. In FIG. 7f theprobe 600 has been removed. As shown in FIG. 7g, 30 minutes afterthawing is complete there is evidence of edema in the left lobe 804 ofthe prostate 800 as indicated by an increase in signal intensity in boththe proton density and T₂ -weighted images. Analysis of T₂ -weightedimaging (not shown here) shows that the increased signal also extendsapproximately 2 mm laterally outside the parenchyma of the prostate 800.

The prostate is then sectioned in a plane corresponding to the NMRimaging plane and prepared for histologic analysis after one week offixing the prostate in a 10% formalin solution. The gross lesionappeared as a dark hemorrhagic semicircular region encompassing 90% ofthe lateral portion of the prostate's left lobe 804, as shown in FIG.8a, is clearly distinguishable from the unaffected portion in the rightlobe 802 of the prostate 800. Histologically, the central part of thelesion is hemorrhagic, edematous and completely necrotic. As shown inFIG. 8b, the boundary of the lesion 803 between the hemorrhagic tissue805 and the healthy tissue 801 is sharp, having a width of less than 0.7mm. At the lesion's boundary 803, the stroma, vascular bed andmyoepithelial cells are intact but the glandular cells are destroyed.Evidence of inflammation is indicated by the presence of sparseinfiltrated neutrofils in the stroma of the lesion's boundary 803.

Comparison of FIGS. 8a and 7d shows that the location of the lesion isaccurately represented by the NMR images. The NMR images at the end offreezing indicate that the cryolesion has encompassed almost all of theleft lobe 804 of the prostate 800. In addition, evidence of edema issupported by the histologic findings. The boundary of the cryolesion isreadlily apparent in the NMR images and corresponds to the location ofthe boundary in the histologic sections. The resolution of the NMRimages is 1 pixel/mm so the accuracy of determining the exact locationof the freezing boundary is on the order of 1 mm. Better resolution canbe obtained by using a higher pixel density or placing the coil on theprobe. The fact that the boundary between necrotic and undamaged tissueis so sharp indicates that NMR images are useful in predicting damagefrom the location of the freezing interface. By monitoring the growth offrozen tissue, the freezing can be stopped when the freezing interfacereaches the boundary of the prostate. Therefore a predictable volume ofdestroyed tissue can be observed in the NMR images.

Interactive control of cryosurgery with NMR.

Freezing can be used both for the preservation of, and the destructionof, biological tissues. The results of the process of freezing andsubsequent thawing depend on the thermal history during the process.Though NMR can be used to determine the position of the freezinginterface, NMR is unable to monitor thermal events in the frozen regionitself. However, the temperature inside the frozen region can becalculated using analytical solutions of the energy equation.

In general, the solution of the heat transfer equation with phasetransformation is difficult because the position of the freezinginterface as a function of time is unknown prior to the solution. Thisintroduces a nonlinearity in the problem, making it difficult to solve.However, when the position of the freezing interface is known, theproblem becomes simple and can be solved by a variety of methods.Imaging the position of the freezing interface with NMR, andincorporating this information in the energy equation transforms thisproblem from one of the more difficult problems of heat transfer into arelatively simple one. The energy equation is ##EQU1## where k is thethermal conductivity, ρ is the density, c is the heat capacity, T is thetemperature, and t is time.

In the NMR-based heat transfer model we need to solve the energyequation in the frozen region only since the heat transfer problem iscompletely specified when the geometry of the boundary and thetemperatures on it are known. NMR images will provide the coordinates ofthe boundary, i.e., the cryoprobe surface and the freezing interface.The boundary temperatures are the probe temperature, which is knownthrough thermistor or optical thermometry measurements (using, forexample, the Luxtron Model 3000 fluoroptic 8 channel system) and thephase transition temperature on the freezing interface which isapproximately -0.56° C. The enthalpy finite element method or the finitedifference method (see Glen E. Myers "Analytical Methods in ConductionHeat Transfer," Genium Publ. Co. Schenectady, N.Y., 1982) can be used tosolve the energy equation. Because knowing the location of the freezinginterface simplifies this problem, the computer program can beimplemented on a work station and run in real time. The problem offinding sufficiently rapid techniques for solution is aided by the factthat during cryosurgy freezing occurs slowly. The freezing interfacevelocity is on the order of 1 mm/min. The accuracy of the solution isalso very good because once tissue is frozen its properties areessentially completely specified by the water content of the specifictissue and the thermal properties of ice. The calculated temperaturedistribution can than be plotted on the imaging monitor as isotherms, orthe temperature history at any point can be correlated to known criteriafor physiological damage to indicate regions that are destroyed orregions that are spared from freezing damage according to thesecriteria.

During cryosurgery, the region adjacent to the frozen tissue will alsoexperience a temperature drop. This temperature drop may, by itself, bedetrimental to the biological tissue. This has been confirmed in theexperiments with the brain. Therefore, the temperature information inthe unfrozen tissue may be important in developing control algorithmsfor cryosurgery.

The temperature in the unfrozen region can be directly monitored fromT1-weighted NMR images. The T1 of tissues is approximately proportionalto temperature in degrees Celsius, i.e., T1 is proportional to (a+0.0074T), where a is a constant that depends on the tissue [Bottomley et al.,"A review of ¹ H NMR relaxation in pathology; are T₁ and T₂ diagnostic?"Mechanical Physics, 14(1), 1-37, 1987] and T is temperature. Theconstant a is approximately 0.53 for brain tissue at 2 Tesla. InversionRecovery (IR) experiments provide a sensitive measure of T1 andtherefore temperature. The NMR signal generated in an IR experiment witha long relaxation time TR is proportional to [1-2 exp (T1/T1)], where T1is the inversion recovery period. The relationship for IR-RARE will beslightly more complic, ated because the condition TR>>TI is notsatisfied. If TI is taken as the T1 at 37° C., then the temperaturedependence of the IR signal is approximately

    1-2 exp (-1/(1+0.01 T))˜0.264-6.57×10.sup.-3 T (4)

over the temperature range of 0° C. to 40° C. Therefore, there isapproximately a five-fold increase in signal intensity as one moves fromthe metabolic tissue temperature of 37° C. toward the freezing interfaceat T=-0.57° C.

Studies on gelatin phantoms demonstrate the ability of IR-RARE [Mulkernet al., "Contrast Manipulation and Artifact Assessment of 2D and 3D RAREsequence," Magnetic Resonance in Medicine 8, 557-566 (1990)] to measurethe one-dimensional temperature distribution in unfrozen regions using athree-chamber apparatus. The outer two chambers are held at twodifferent temperatures by circulating fluids, and the gelatin is placedin the center chamber. The temperature in one outer chamber is held at20° C. while the temperature in the other is decreased stepwise to -10°C. in 2° C. intervals. Heat transfer theory predicts that at thermalequilibrium, the temperature will have a linear temperature profileacross the gelatin. At each step the gelatin was allowed to come tothermal equilibrium before proceeding to the next, thus establishing aseries of known temperature gradients in the gelatin. MR images usingIR-RARE (T1=800 ms; recycle delay=2 sec; 31 echoes) are acquired bothduring cool down and during freezing. With this inversion time T1, thesignal intensity decreases as temperature increases. FIG. 9 shows thesignal intensity versus temperature taken from a two-dimensional IR-RAREimage of the gel with one end held at 0° C. and the other at 20° C. Thetemperatures are measured by thermocouples in the gel. A lineartemperature gradient is expected. A second order polynomial is fit tothe data. Alternatively, a model based on the spin dynamics of theIR-RARE experiment may be employed. The correlation between theory andexperiment in FIG. 9 indicates that IR-RARE experiments can achieve highaccuracy in the temperature range of interest for cryosurgery.

During slow one-dimensional freezing (˜0.5 mm/min) the gelatin remainsin thermal equilibrium because the heat transfer rate in the gelatin ismuch higher than the freezing rate. A zeroth order perturbation solutionfor the temperature distribution, T(x) in the unfrozen gelatin is:##EQU2## where T_(ph) is the phase transition temperature (0° C.), T_(H)is the temperature of the hot side (20° C.), a is the thickness of thesample (25 cm), s(t) the thickness of the ice, and x is the distancealong the direction of freezing starting from the cold side. For thecase studied this equation reduces to: ##EQU3## Therefore a lineartemperature distribution in the unfrozen gelatin is expected. FIG. 10ashows signal intensity versus position, 8 minutes and 14 minutes afterthe gel begins to freeze. No signal is detected from the frozen gel, sothe position of the interface is easily located.

FIG. 10a shows temperature distributions calculated by using the curvein FIG. 9 as a calibration. Data for the 7 mm thick ice sample are shownalong with the line predicted by theoretical calculation 10b. Theplotted points in FIG. 10b start at the boundary of the frozen gel.Overall, there is agreement with the IR-RARE experiments within theaccuracy of the zeroth order theoretical solution. The IR-RAREexperiments showed a linear temperature increase across the unfrozengelatin. A line is drawn through the points in FIG. 10b to indicate thelinearity. The basic relations for predicting the temperature in othertissues types are the same.

NMR interactive cryosurgery control

One of the problems associated with cryosurgery is the control of thefreezing interface propagation. Lack of control can result inundesirable freezing of sensitive tissue, particularly when multipleprobes are used. NMRmonitored interactive cryosurgery can providesurgeons with information during the procedure that can facilitate moreaccurate application of the procedure to compensate for errors in thetreatment planning process, thereby avoid over-freezing orunder-freezing, and assuring a freezing protocol that results in assureddestruction of tissue. The method of the present invention employs asystem that monitors the position of the freezing interface and thetemperature in the unfrozen region using NMR, calculates the temperaturedistribution in the frozen region as described in the previous sectionand the velocity of the freezing interface, and displays this additionalinformation superimposed on the NMR slices. Although cryosurgical probesmay not be moved during the freezing process, their temperature can beadjusted to achieve a desirable thermal history or freezing interfacevelocity. By observing the progress of the frozen region and thetemperature distribution in the tissue the flow of cryogen or itstemperature can be adjusted to achieve a desired result either throughmanual control by the surgeon or though an online feedback controlsystem.

The technique to determine the velocity of the freezing interface usesthe NMR-based temperature model in the frozen region described above andthe NMR measurement of the temperature in the unfrozen region alsodescribed above. (The temperature in the unfrozen region is obtainedfrom NMR thermometry. The temperature in the frozen region is obtainedby solving the NMR-based heat transfer model. ) The position andvelocity of the interface (calculated from the temperature gradient) isobtainable from a single IR-RARE image which provides complete dynamiccharacterization. The temperature distributions can be used withFourier's law to determine heat fluxes at the freezing interface.Thereafter, the velocity of the freezing interface can be determined bysolving the equation

    q.sub.u -q.sub.f =ρ.sub.o ·L v.sub.n

where q_(u) is the heat flux in the unfrozen region, q_(f) is the heatflux in the frozen region, ρ_(o) is the density, L is the latent heat offusion, and v_(n) is the required velocity of the freezing interface.The velocity of the interface is used to determine if a particularsensitive tissue is in imminent danger of being frozen.

In summary, apparatus and methods for magnetic resonance assistedcryosurgery have been described.

The present invention has been described in terms of a preferredembodiment. The invention, however, is not limited to the embodimentdepicted and described. Many variations are within the scope of theinvention. For instance, the need to visualize the process of freezinginside tissue is not limited only to cryosurgery, but is also importantin any other application where biological materials are frozen.Therefore, another application is preservation of biological materialsin medicine and biotechnology, such as cells, cells in suspension,tissues, such as pancreatic islets, skin, whole organs or even wholeanimals, by freezing or vitrification. Another application is monitoringthe process of freezing during preservation of foods such as meat, fish,vegetables, fruit, or dough. Furthermore, the need to monitor tissuedamage is useful for surgical and medical purposes other thancryosurgery, such as laser surgery and radiation therapy. Othervariations within the scope of the present invention include:minimization techniques other than the downhill simplex method may beused to determine an optimal placement of the cryoprobes and theoptimization of other parameters of the cryosurgery; the temperaturehistories of the cryoprobes may be held constant while the positions ofthe cryoprobes are optimized; the positions of the cryoprobes may beheld constant while the temperature histories of the cryoprobes may beoptimized; the stereotactic device may be constructed of othermaterials, including plexiglass, fiberglass, plastic, rubber, etc.; thedimensions of the cryoprobe and coils are not special or unique andnumerous other dimensions and configurations with coils attached to theprobe are possible; the stereotactic device may hold a plurality ofprobes; the stereotactic device may incorporate other means forpositioning and securing the cryoprobes; radio frequency coils may bepositioned in the cryosurgical region without being attached to thecryoprobe or cryoprobes; the stereotactic device may utilize a differentconfiguration of the position/orientation markers; the probe of thepresent invention can be used with a variety of surgical techniques,such as cauterization, heating, cooling, laser treatment or mechanicalresection, suction and other alterations of tissue; tissue damage may bemonitored using nuclei other than phosphorus-31 and sodium 23; thecryogen is not limited to liquid nitrogen; the temperature distributionin the freezing region may be calculated without using T1 data; or theMR coil may be mounted on the cryoprobe in a different manners, at adifferent location, or in a different orientation.

Rather, the scope of the invention is defined by the appended claims.

What is claimed is:
 1. An apparatus for high-resolution magneticresonance monitoring of cryosurgery in a subject tissue, comprising:amagnet producing a magnetic field to which said subject tissue isexposed; a cryoprobe located in said magnetic field and having anintracorporeal end, an exterior surface, a cavity, an inlet forintroduction of a cryogen to said cavity, an outlet for exhaust of saidcryogen from said cavity, and a thermally conducting region between saidcavity and an active region on a portion of said exterior surface forapplication to said subject tissue; and a magnetic resonance radiofrequency coil mounted on said cryoprobe within a distance less thanseveral times a diameter of said coil from said active region forproviding a magnetic resonance image of said subject tissue.
 2. Theapparatus of claim 1 wherein said magnetic resonance frequency coil islocated within a distance less than said diameter from said activeregion of said cryoprobe.
 3. The apparatus of claim 1 wherein said coilis tuned for proton magnetic resonance imaging.
 4. The apparatus ofclaim 1 wherein said coil is tuned for sodium magnetic resonanceimaging.
 5. The apparatus of claim 1 wherein said coil is tuned forphosphorous magnetic resonance imaging.
 6. A surface probe, comprising:acryoprobe having an intracorporeal end and an exterior surface, acavity, an inlet for introduction of a cryogen to said cavity, an outletfor exhaust of said cryogen from said cavity, and a thermally conductingregion between said cavity and an active region on a portion of saidexterior surface for application to a subject tissue; and a firstmagnetic resonance radio frequency coil mounted on said cryoprobe withina first distance less than several times a diameter of said coil fromsaid active region of said cryoprobe for providing a first magneticresonance image of said subject tissue.
 7. The surface probe of claim 6wherein said first coil is mounted in said thermally conductive region.8. The surface probe of claim 7 further includinga coil mount extendinglaterally from the external surface of said cryoprobe; and a secondmagnetic resonance radio frequency coil mounted on said coil mount andwithin a second distance less than several times a diameter of saidsecond coil from said active region for providing a second magneticresonance image of said subject tissue.
 9. The surface probe of claim 6further including a coil mount extending laterally from the externalsurface of said cryoprobe, said first coil mounted on said coil mount.